Convenient and efficient synthesis of pyrazole-based DHODase inhibitors from 3-aryl-4-cyanosydnone

Article abstract of DOI:10.1055/s-2006-939041

Pyrazole-based DHODase inhibitors have been efficient and conveniently synthesized in 51-60% yield from 3-(p-aryl)-4-cyanosydnone via regioselective 1,3-diploar cycloaddition followed by an amidation and a Ritter reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-939041

LETTER
901
Convenient and Efficient Synthesis of Pyrazole-Based DHODase Inhibitors
from 3-Aryl-4-cyanosydnone
S
ynthesis of Py
n
-
DH
O
D
M
a
b
c
Sustainable Environment Research Center, National Cheng Kung University, 500 (Sec. 3) An-ming Rd., Tainan City 709, Taiwan
Department of Chemistry, National Cheng Kung University, 1 Ta Hsueh Rd., Tainan 70101, Taiwan
Nan Jeon Institute of Technology, 178 Chaocin Rd., Yanshuei Township, Tainan County 737, Taiwan
Fax +886(6)3840960 ; E-mail: wong99@mail.ncku.edu.tw
Received 30 December 2005
acid/ester product.6 A subsequent amidation step results in
the pyrazole DHODase inhibitor 1, which can be prepared
in less than 50% yield. The core pyrazole 1 was also
prepared on solid support, however, this methodology is
generally performed only on a small scale.7 We report
the regioselective 1,3-dipolar cycloaddition of 3-aryl-4-
cyanosydnone (2 or 7) to propargylic esters using the
highly hindered diphenylmethyl propiolate. This provided
only the diphenylmethyl 5-cyano-1-aryl-1H-pyrazole-3-
carboxylate 5d or 9 without any of the regioisomer 6.8
Subsequent amination and Ritter reactions provided a
convenient and efficient access to pyrazole DHODase
inhibitors.
Abstract: Pyrazole-based DHODase inhibitors have been efficient
and conveniently synthesized in 51–60% yield from 3-(p-aryl)-4-
cyanosydnone via regioselective 1,3-diploar cycloaddition fol-
lowed by an amidation and a Ritter reaction.
Key words: sydnones, 1,3-dipolar cycloaddition, propargylic ester,
pyrazole, DHODase inhibitors
Helicobacter pylori is a gram-negative microaerophilic
bacterium that infects up to 50% of the world’s human
population.1 Helicobacter pylori resides in the acidic sur-
roundings of the stomach, utilizing high urease enzyme
activity to provide a locally alkaline environment. Inhibi-
tion of a key enzyme of the de novo pyrimidine biosyn-
Sydnones9 undergo smooth cycloaddition with propargyl-
ic esters to give pyrazoles.10–15 The reaction involves a
1,3-dipolar cycloaddition of the sydnones, which behave
as cyclic azomethine imines. The initially formed cy-
cloadducts readily release carbon dioxide to produce a
mixture of five-membered regioisomeric pyrazoles. To
optimize the ratio of regioisomers (5/6), 3-(p-ethoxyphen-
yl)-4-cyanosydnone 2 was treated with unsymmetrically
substituted propargylic esters in chlorobenzene at reflux
for 48 hours (Scheme 1). The reaction pathway involves a
cycloaddition to a sydnone to give two N-bridged inter-
mediates 3 and 4. The regiochemistry of cycloaddition
should be controlled by the steric effect of the bulky sub-
stituent R2 of propargylic esters and the 4-cyano group of
sydnone 2. As the size of the R2 substituent of propargylic
esters was increased (Et, CH2Ph, and t-Bu), the regioiso-
meric ratio (5/6) improved from 57:43 to 78:22 (Table 1).
The structure assignment of the regioisomers (5/6) was
thetic
pathway,
dihydroorotate
dehydrogenase2
(DHODase), could selectively kill this H. pylori bacteri-
um without affecting human cells or other bacterial spe-
cies.3 In 2000, Copeland et al.,3 reported that pyrazole-
based compounds 1 are potent and selective inhibitors of
the dihydroorotate dehydrogenase of H. pylori (H. pylori
DHODase) but do not inhibit the cognate enzymes from
gram-positive bacteria or humans (Figure 1).
O
R2HN
R1O
N
NHR3
N
O
1
Figure 1
1
made on the basis of their characteristic H NMR spec-
There have been a few methods reported for the synthesis
of the carboethoxy-pyrazole core. Ashton et al.4 reported
a regioselective synthesis of 1H-pyrazole-5-carboxylate
from 2,4-diketo esters, but, in order to direct the initial at-
tack of the arylhydrazine on the 4-carbonyl, the 2-carbon-
yl had to be protected. The pyrazole monoacid/monofuran
cores were successfully synthesized by solution phase
synthesis.5 The furan was oxidized to a carboxylic acid
with sodium periodate and ruthenium(III) chloride or po-
tassium permanganate to provide the desired pyrazole
trum. Particular attention was given to the chemical shift
of the pyrazole proton. The ring proton in the 3-carbo-
ethoxy-substituted isomers (5a–d) appeared 1.2–1.3 ppm
upfield relative to the 4-carboethoxy-substituted isomer
(6a–c). However, when 3-(p-ethoxyphenyl)-4-cyanosyd-
none (2) was reacted with diphenylmethyl propiolate
(R2 = CHPh2), only a single product, diphenylmethyl
5-cyano-1-(p-ethoxyphenyl)-1H-pyrazole-3-carboxylate
(5d), was identified and isolated in 85% yield.
As a result, 3-aryl-4-cyanosydnones 2 and 7 were treated
with diphenylmethyl propiolate in chlorobenzene at re-
flux (ca. 130 °C) and the progress of the reaction was
monitored by carbon dioxide evolution without isolating
the bicyclic intermediate 8 (Scheme 2). After work-up
SYNLETT 2006, No. 6, pp 0901–0904
Advanced online publication: 14.03.2006
DOI: 10.1055/s-2006-939041; Art ID: W12105ST
© Georg Thieme Verlag Stuttgart · New York
0
4.
0
4.
2
0
0
6

902
E.-M. Chang et al.
LETTER
Ar
N
O
N
C
Ar
O
O
N
C
NC
N
OR2
O
H
O
N
OR2
O
O
N
+
EtO
O
N
N
chlorobenzene
48 h, reflux
O
R2O
3
4
2
O
NC
NC
N
5a, 6a R2 = Et
5b, 6b R2 = t-Bu
5c, 6c R2 = CH2Ph
OR2
N
EtO
EtO
+
OR2
N
N
5d
R2 = CHPh2
O
5
6
Scheme 1
Table 1 1,3-Dipolar Cycloaddition of the Sydnonea
by treatment with benzylamine. We attempted to perform
the Ritter reaction by treating compounds 10a and 10b
with cyclohexanol in refluxing formic acid,18 however,
the resultant reaction mixture was complex and only
provided a small amount of the expected N-alkylation
products. The Ritter reaction was modified19,20 by using
boron trifluoride as a catalyst under aprotic and non-aque-
ous conditions. Compound 10a or 10b was added to a
solution of cyclohexanol and boron trifluoride etherate in
chlorobenzene and heated at reflux for 72 hours. After
work-up and purification, the corresponding pyrazole
DHODase inhibitor analogues 11a and 11b were obtained
in 70% and 76% yields, respectively (Scheme 2).
Entry
R2
Regioisomeric ratio
(%)a
Isolated yield of
5 and 6 (%)
5a–d
58
6a–c
42
1
2
3
4
Et
80
79
76
85d
t-Bu
78
57
22
CH2Ph
CHPh2
43
c
ca. 100
–
a Sydnone 2, unsymmetrically substituted propiolate, chlorobenzene,
reflux, 48 h.
b The 5/6 ratios were determined by 1H NMR spectroscopy.
c Not detected.
In conclusion, we have developed an efficient method to
control the regioselectivity of the 1,3-dipolar cycloaddi-
tion of bulky diphenylmethyl propiolate with 3-aryl-4-
cyanosydnone (2 or 7), which was applicable to the syn-
thesis of DHODase inhibitor analogues 11a and 11b. The
cyclized 5-cyano-1-aryl-1H-pyrazole-3-carboxylate (5d
or 9) was obtained as a single isomer. After amidation and
Ritter reaction, compounds 5d and 9 were converted to
compounds 11a and 11b in 51% and 60% yields, respec-
tively, from 3-(p-aryl)-4-cyanosydnone 2 and 7.
d Only 5d was isolated.
and column chromatography, diphenylmethyl 5-cyano-
1H-pyrazole-3-carboxylates 5d and 9 were obtained as
the single products in 85% and 80% yields, respectively.
The carboxylic ester 5d and acid 9 were directly con-
verted to the corresponding secondary amides 10a and
10b in excellent yields (93% and 91%, respectively)16,17
Ar
N
O
N
C
NC
O
O
H
O
OCHPh2
N
N
R
O
N
chlorobenzene, 48 h,
reflux
O
Ph2HCO
2 R = OEt
7 R = H
8
NC
N
NC
NH2CH2Ph
R
N
R
NHCH2Ph
OCHPh2
N
xylene, 72 h, reflux
N
O
O
10a R = OEt, 93%
10b R = H, 91%
5d R = OEt, 85%
R = H, 80%
9
cyclohexanol, BF3·OEt2
O
11a R = OEt, 76%
11b R = H, 70%
HN
chlorobenzene, 72 h, reflux
R
N
N
NHCH2Ph
O
Scheme 2 Synthesis of the pyrazole-based DHODase inhibitors.
Synlett 2006, No. 6, 901–904 © Thieme Stuttgart · New York

LETTER
Synthesis of Pyrazole-Based DHODase Inhibitors
903
(11) Padwa, A.; Burgess, E. M.; Gingrich, H. L.; Roush, D. M. J.
Org. Chem. 1982, 47, 786.
References and Notes
(1) Covacci, A.; Telford, J. L.; Giudice, G. D.; Parsonnet, J.;
Rappuoli, R. Science (Washington, D.C.) 1999, 284, 1328.
(2) Copeland, R. A.; Davis, J. P.; Dowling, R. L.; Lombardo, D.;
Murphy, K. B.; Patterson, T. A. Arch. Biochem. Biophys.
1995, 323, 79.
(3) Copeland, R. A.; Marcinkeviciene, J.; Haque, T. S.; Kopcho,
L. M.; Jing, W.; Wang, K.; Ecret, L. D.; Sizemore, C.;
Amsler, K. A.; Foster, L.; Tadesse, S.; Combs, A. P.; Stern,
A. M.; Trainor, G. L.; Slee, A.; Rogers, M. J.; Hobbs, F. J.
Biol. Chem. 2000, 275, 33373.
(4) Ashton, W. T.; Doss, G. A. J. Heterocycl. Chem. 1993, 30,
307.
(5) Lam, P. Y.; Clark, C. G.; Dominguez, C.; Fevig, J. M.; Han,
Q.; Li, R.; Pinto, D. J.-P.; Pruitt, J. R.; Quan, M. L. The Du
Pont Merck Pharmaceutical Company U.S.A. W09857951,
1998.
(12) Huisgen, R. Bull. Soc. Chim. Fr. 1965, 3431.
(13) Huisgen, R.; Gotthardt, H. Chem. Ber. 1968, 101, 1059.
(14) Gotthardt, H.; Huisgen, R. Chem. Ber. 1968, 101, 552.
(15) Hans, G.; Friedemann, R. Chem. Ber. 1979, 112, 1193.
(16) Ranu, B. C.; Dutta, P. Synth. Commun. 2003, 33, 297.
(17) Amidation; General Procedure. Benzylamine (8.0 mmol)
was added to a solution of 3-aryl-4-cyanosydnone (5d or 9,
2.0 mmol) in xylene (15 mL) and the resulting solution was
heated to reflux for 72 h under N2. After the reaction was
completed, the reaction mixture was concentrated under
reduced pressure to remove xylene. The residue was
dissolved in CH2Cl2 (2.0 mL) and purified by column
chromatography (silica, EtOAc–hexanes, 4:1) to provide the
corresponding product 10a or 10b in 93% and 91% yields,
respectively.
10a: Mp 142–144 °C; IR (KBr): 3331 (s, NH), 2237 (m,
CN), 1655 (m, C=O) cm–1; 1H NMR (CDCl3, 300 MHz): d =
1.34 (t, J = 6.8 Hz, 3 H, CH3), 4.10 (q, J = 6.8 Hz, 2 H, CH2),
4.44 (d, J = 6.3 Hz, 2 H, NCH2), 7.13 (d, J = 9.0 Hz, 2 H,
ArH), 7.20–7.26 (m, 1 H, ArH), 7.29–7.31 (m, 4 H, ArH),
7.66 (s, 1 H, pyrazole-H), 7.71 (d, J = 9.0 Hz, 2 H, ArH),
9.14 (t, J = 6.3 Hz, 1 H, NH); 13C NMR (CDCl3, 75 MHz):
d = 15.83, 43.51, 65.01, 111.99, 116.38, 117.03, 117.28,
126.94, 128.15, 128.67, 169.59, 131.97, 140.63, 148.63,
160.70, 160.93; Anal. Calcd for C20H18N4O2: C, 69.35; H,
5.24; N, 16.17. Found: C, 69.40; H, 5.35; N, 16.02.
10b: Mp 95–96 °C; IR (KBr): 3281 (s, NH), 2232 (m, CN),
1649 (m, C=O) cm–1; 1H NMR (CDCl3, 300 MHz): d = 4.45
(d, J = 6.2 Hz, 2 H, NCH2), 7.20–7.27 (m, 1 H, ArH), 7.29–
7.31 (m, 4 H, ArH), 7.55–7.65 (m, 3 H, ArH), 7.77 (s, 1 H,
pyrazole-H), 7.79 (d, J = 9.0 Hz, 2 H, ArH), 9.18 (t, J = 6.2
Hz, 1 H, NH); 13C NMR (CDCl3, 75 MHz): d = 43.52, 11.94,
116.90, 117.83, 125.17, 128.18, 128.68, 129.61, 131.05,
131.21, 139.03, 140.55, 148.98, 160.90; Anal. Calcd for
C18H14N4O: C, 71.51; H, 4.67; N, 18.53. Found: C, 71.54; H,
4.74; N, 18.44.
(6) Danishefsky, S. J.; Pearson, W. H.; Segmuller, B. E. J. Am.
Chem. Soc. 1985, 107, 1280.
(7) Haque, T. S.; Tadesse, S.; Marcinkeviciene, J.; Rogers, M.
J.; Sizemore, C.; Kopcho, L. M.; Amsler, K.; Ecret, L. D.;
Zhan, D. L.; Hobbs, F.; Slee, A.; Trainor, G. L.; Stern, A. M.;
Copeland, R. A.; Combs, A. P. J. Med. Chem. 2002, 45,
4669.
(8) 1,3-Dipolar Cycloaddition; General Procedure. Ethyl,
tert-butyl, benzyl, or diphenylmethyl propiolate (0.25 g,
2.0 equiv) was added to a solution of 3-(p-ethoxyphenyl)-4-
cyanosydnone (2, 0.23 g, 1.0 equiv) in chlorobenzene (10
mL) and heated to reflux under N2 for 48 hours. After the
reaction was complete, the reaction mixture was
concentrated under reduced pressure to remove
chlorobenzene. The residue was dissolved in CH2Cl2 (2.0
mL) and purified by gravity column chromatography (silica,
EtOAc–hexanes, 15:85) to provide the corresponding
products 5a–d and 6a–c.
5d: IR (KBr): 3031 (s), 2980 (s), 2229 (m, CN), 1726 (m,
C=O) cm–1; 1H NMR (CDCl3, 300 MHz): d = 1.35 (t,
J = 10.4 Hz, 3 H, CH3), 3.98 (q, J = 10.4 Hz, 2 H, CH2), 6.92
(d, J = 7.7 Hz, 2 H, ArH), 7.08 (s, 1 H, Ph2CH), 7.15 (s, 1 H,
pyrazole-H), 7.20–7.35 (m, 8 H, ArH), 7.41 (d, J = 7.7 Hz, 2
H, ArH), 7.47–7.54 (m, 2 H, ArH); 13C NMR (CDCl3, 75
MHz): d = 14.66, 63.95, 77.92, 110.11, 115.15, 115.65,
117.82, 124.92, 124.97, 127.22, 128.15, 128.57, 128.62,
130.95, 139.53, 139.59, 144.21, 159.65, 159.99; Anal. Calcd
for C26H21N3O3: C, 73.74; H, 5.00; N, 9.92. Found: C, 73.65;
H, 5.12; N, 9.96.
9: IR (KBr): 3020 (s), 2985 (s), 2932 (m, C=N), 1736 (m,
C=O) cm–1; 1H NMR (CDCl3, 300 MHz): d = 6.90 (d,
J = 7.7 Hz, 2 H, ArH), 7.07 (s, 1 H, Ph2CH), 7.13 (s, 1 H,
pyrazole-H), 7.21–7.37 (m, 8 H, ArH), 7.41 (d, J = 7.7 Hz,
2 H, ArH), 7.47–7.54 (m, 3 H, ArH); 13C NMR (CDCl3, 75
MHz): d = 77.89, 110.11, 115.13, 115.64, 117.80, 124.90,
124.95, 126.45, 127.19, 128.15, 128.56, 128.59, 130.92,
139.49, 139.55, 144.20, 159.97; Anal. Calcd for
C24H17N3O2: C, 75.97; H, 4.52; N, 11.08. Found: C, 75.92;
H, 4.56; N, 11.12.
(18) (a) Krimer, L. I.; Cota, D. Org. React. 1969, 17, 213.
(b) Bishop, R. In Comprehensive Organic Synthesis, Vol. 6;
Trost, B. M.; Fleming, I.; Winterfeldt, E., Eds.; Pergamon:
Oxford, 1991, 261. (c) Gullickson, G. C.; Lewis, D. E.
Synthesis 2003, 681.
(19) Firouzabadi, H.; Sardarian, A. R.; Badparva, H. Synth.
Commun. 1994, 24, 601.
(20) Ritter Reaction; General Procedure A solution of
cyclohexanol (4.0 mmol) and BF3·OEt2 (4.0 mmol) in
chlorobenzene was stirred at r.t. for 0.5 h. Compound 10a or
10b (1.0 mmol) was added to the reaction mixture, which
was heated to reflux for 72 h. The solution was neutralized
with Et3N and the reaction mixture was concentrated under
reduced pressure to remove chlorobenzene. The residue was
dissolved in CH2Cl2 (2.0 mL) and purified by column
chromatography (silica, EtOAc–hexanes, 1:4) to provide the
corresponding product 11a or 11b as light-yellow solids in
76% and 70% yields, respectively.
11a: Mp 146–148 °C; IR (KBr); 3322 (s, NH), 2929 (m),
2852 (m), 1647 (m) cm–1; 1H NMR (CDCl3, 300 MHz): d =
1.09–1.21 (m, 4 H), 1.33 (t, J = 6.9 Hz, 3 H, CH3), 1.52–1.73
(m, 6 H), 3.57 (m, 1 H, NCH), 4.09 (q, J = 10.1 Hz, 2 H,
CH2), 4.42 (d, J = 5.9 Hz, 2 H, NCH2), 6.99 (d, J = 8.6 Hz, 2
H, ArH), 7.22 (d, J = 8.6 Hz, 2 H, ArH), 7.30 (d, J = 3.7 Hz,
4 H, ArH), 7.33 (s, 1 H, ArH), 7.36 (s, 1 H, pyrazole-H), 8.47
(9) For the preparation of sydnones, see: (a) Yeh, M.-Y.; Tien,
H.-J.; Huang, L.-Y.; Chen, M.-H. J. Chin. Chem. Soc. 1983,
30, 29. (b) Thoman, C. J.; Voaden, D. J.; Hunsberger, I. M.
J. Org. Chem. 1964, 29, 2044. (c) Dallacker, F.; Kern, J.
Chem. Ber. 1966, 99, 3830. (d) Kuo, W.-F.; Lin, I.-T.; Sun,
S.-W.; Yeh, M.-Y. J. Chin. Chem. Soc. 2001, 48, 769.
(e) Hans, G.; Friedemann, R. Liebigs Ann. Chem. 1979, 1,
63; Chem. Abstr. 1979, 90, 203976.
(d, J = 7.7 Hz, 1 H, NH), 8.89 (t, J = 5.9 Hz, 1 H, NH); 13
NMR (CDCl3, 75 MHz): d = 15.02, 25.06, 25.55, 32.45,
C
(10) Totoe, H.; McGowin, A. E.; Turnbull, K. J. Supercritical
Fluids 2000, 18, 131.
42.47, 48.54, 63.88, 108.50, 114.58, 126.68, 127.15, 127.72,
128.66, 133.18, 139.35, 140.10, 146.33, 158.28, 158.72,
Synlett 2006, No. 6, 901–904 © Thieme Stuttgart · New York

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E.-M. Chang et al.
LETTER
161.22; Anal. Calcd for C26H30N4O3: C, 69.93; H, 6.77; N,
12.55. Found: C, 69.79; H, 6.85; N, 12.40.
1 H, pyrazole-H), 8.54 (d, J = 7.8 Hz, 1 H, NH), 8.92 (t,
J = 6.1 Hz, 1 H, NH); 13C NMR (CDCl3, 75 MHz): d =
25.91, 26.39, 33.26, 43.37, 49.49, 109.67, 126.01, 128.08,
128.60, 129.56, 129.67, 130.04, 140.36, 140.86, 140.96,
147.57, 159.24, 162.10; Anal. Calcd for C24H26N4O2: C,
71.62; H, 6.51; N, 13.92. Found: C, 71.42; H, 6.60; N, 13.77.
11b: Mp 142–143 °C; IR (KBr): 3281 (s, NH), 2927 (s),
1644 (m, C=O) cm–1; 1H NMR (CDCl3, 300 MHz): d = 1.07–
1.29 (m, 4 H), 1.53–1.75 (m, 6 H), 3.59 (m, 1 H, NCH), 4.44
(d, J = 6.1 Hz, 2 H, NCH2), 7.20–7.25 (m, 2 H, ArH), 7.30
(d, J = 4.2 Hz, 4 H, ArH), 7.42–7.46 (m, 4 H, ArH), 7.51 (s,
Synlett 2006, No. 6, 901–904 © Thieme Stuttgart · New York